My laboratory focuses on gene expression, and how misregulation of expression, rather  than gene mutation, can contribute to disorders including autism, epilepsy, and Rett syndrome.  Our goals are to identify genes that are inappropriately expressed, either in amount, location or developmental timeframe within neurodevelopmental disorders. This will allow us to directly characterize the consequences of misexpression at the cellular and organismal level, and will highlight pathways critical to the development of these disorders that may be impaired in other individuals, leading to the identification of additional genetic defects, and to novel or more specific treatment options.

Chromosome 15 contains a large cluster of genes involved in neural development and function, many of which are imprinted, an epigenetic phenomenon whereby a gene is expressed only from the chromosome inherited from either the mother or the father. The gene for Angelman syndrome, for example, is only expressed from maternal ch15 in neurons.  As a result, different phenotypes result if genes are deleted, mutated or otherwise altered on a maternal ch15 vs. a paternal ch15. Proper regulation of imprinted genes is mediated by proteins such as MeCP2, which is mutated in Rett syndrome. Ch15 also contains several autism candidate genes, and the overlap between autism, Rett syndrome and Angelman syndrome may be due to the interplay between MeCP2 and the regulation of ch15 gene expression levels.  We are using both patient samples and mouse models to determine the effects of loss of MeCP2 on the expression patterns of autism candidate genes. We are also developing RNAi-based mouse models to analyze the social and behavioral effects of aberrant expression of autism candidate genes.

Many of these patients will also develop seizures, and non-syndromic pediatric epilepsy is itself a major health concern. Most epilepsy is not due to an underlying gene mutation, but may develop after an ‘insult’ such as injury or infection. An additional interest in my laboratory is to identify the gene expression differences that underlie epileptogenic vs. normal tissue, in particular focusing on ion-channel and neurotransmitter receptor subunit genes that can directly contribute to aberrant neuronal electrical activity. Comparison between individuals and seizure classes will help identify changes that may underlie seizure generation or are secondary to epileptogenesis. These results will guide studies in mouse models, and provide the possibility to tailor pharmacologic intervention for optimal seizure management.